Major depressive disorder (MDD) has been associated with abnormally reduced function of central serotonergic systems by various types of evidence. One instructive paradigm for investigating the relationship between serotonergic function and depression has involved the mood response to tryptophan depletion (TD), achieved by oral loading with all essential amino acids excepting the 5-HT precursor, tryptophan. We obtained preliminary evidence that the mood lowering effect of TD depends upon the genotype for a functional polymorphism in the promoter region of the 5-HT transporter (5-HTT), designated 5-HTTLPR, as well as upon family history. In healthy females the s-allele and a positive family history for mood disorders appeared to be additive risk factors for the development of depressive symptoms during TD. The current study employs quantitative PET imaging of cerebral blood flow (CBF) and glucose metabolism to investigate the effect of variant 5-HTTLPR genotypes on the neurophysiological response to TD. The current study examines the relationship between 5-HTTLPR genotypes and the TD effect on PFC metabolic activity. We determine whether under TD the reduction in PFC metabolism in response to TD will be occur to a greater extent in subjects with the s/s allele, and in subjects with a single s allele plus a family history of depression. We also examine whether this reduction in PFC metabolic activity is unique to subjects who develop depressive symptoms during TD. In addition, based upon evidence that 5-HT inhibits neuronal activity in the amygdala, and modulates transmission of emotionally-salient sensory information from the sensory cortices to the amygdala, we test the hypothesis that in MDD, reduced serotonin function associated with TD may disinhibit the amygdala response to sensory stimulation. This hypothesis is explored by assessing the physiological responses of the amygdala to sensory stimuli that normally activate the amygdala, namely pictures of human faces that show fearful or sad emotional expressions. We are particularly interested in determining whether the amygdala CBF response to emotional stimuli during TD is most prominently increased in subjects carrying the s-allele of the 5-HTTLPR, and whether it is unique to subjects who develop depressive symptoms during TD. Thirty-six unmedicated-remitted subjects with MDD and 36 healthy controls are studied in a double-blind, placebo-controlled, randomized (according to 5-HTTLPR genotype) crossover study.